The focus of this proposal is on ORMDL-3, a protein localized to chromosome 17q21, which has been highly linked to asthma in several genome wide association studies. The aim of this project is on understanding how ORMDL3 expressed in bronchial smooth muscle cells influences smooth muscle contraction through activation of SERCA2b. The study will utilize human lung smooth muscle cells in vitro, human lung sections of asthmatics ex vivo, and in vivo studies examining mice expressing the human ORMDL3 transgene in smooth muscle to determine how ORMDL3 activates SERCA2b to regulate smooth muscle phenotypic changes and contraction in vitro, and influences levels of smooth muscle and airway hyperreactivity in vivo. Overall, these studies will provide important insight into how ORMDL3, a gene highly linked to asthma, contributes to smooth muscle remodeling and asthma.